CONCLUSIONS
There is still a significant limitation in the medical interpretation of
genetic testing for complex, non-monogenic phenotypes. Our study shows
that almost half of the EFHC1 variants found in patients with
GGEs remained as VUS after applying the modified classification proposed
in this study using the ACMG/AMP guidelines. In addition, the only
variant that could be classified as ‘pathogenic’ (c.685T>C)
was found in only 3% of the JME patients in our current study and in
1–5% in the reported literature (Annesi et al., 2007; Podewils, 2015;
Raju et al., 2017; Stogmann et al., 2006). Our results, together with
previous evidence, indicate that EFHC1 variants are currently
best classified as a risk factor—not a causal, major gene—for JME
and other GGEs. Given that the interpretation of genetic testing results
for EFHC1 variants is complex and offers little information for
clinical decision-making, we suggest that the inclusion of EFHC1in gene panels for genetic testing should be limited to research
purposes.